Suppressor of cytokine signal 3 and IL28 genetic variation predict the viral response to peginterferon and ribavirin
ABSTRACT Aim: The aim of this study was to investigate the relationship among the expression of suppressor of cytokine signaling 3 (SOCS 3) in the liver, the SNPs in the IL28B locus, and the outcome of interferon therapy.Methods: Prior to interferon treatment, we immunostained 67 liver specimens from chronic hepatitis C (CHC) patients who were receiving peginterferon alpha-2b/ribavirin therapy for suppressor of cytokine signaling 3 (SOCS3), and compared the expression of SOCS3, IL28 polymorphisms and other clinical factors between the patients and compared their eventual outcomes.Results: Significant differences between the low SOCS3 group and high SOCS3 group were found in age, as well as in the platelet, transaminase, gamma-glutamyl transpeptidase levels. The incidence of high SOCS3 was not significantly different between subjects with the TT genotype and the TG genotype (TT : TG = 71%:29%, P = 0.250). In a multivariate analysis, age (≥65 years old) (odds ratio 0.221 [0.120–0.966], P = 0.045), IL28B gene (genotype TT) (odds ratio 5.422 [1.254–23.617], P = 0.024) and SOCS3 (high) (odds ratio 0.308 [0.104–0.948], P = 0.040) were significant predictors of the interferon response. In patients with the TT genotype, those with low SOCS3 immunostaining showed a high sustained virological response (69%), while the sustained virological rate was low (27%) in the patients with high SOCS3 immunostaining.Conclusions: Using a combination of the SOCS3 immunostained area in the liver and the expression of IL28B single nucleotide polymorphisms might be a useful predictor of hepatitis C virus clearance by interferon therapy.
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ABSTRACT: Many studies have been published on the association between single nucleotide polymorphisms (SNP) near the IL28B gene and response to the combined treatments of pegylated-interferon (PegIFN) and ribavirin (RBV) in chronic HCV-infected patients, but without identical conclusions. The aim of this study was to assess impact of the IL28B polymorphisms on the effect of HCV standard treatment using meta-analysis based method. Association studies between polymorphisms of rs12979860 or rs8099917 and response to PegIFN/RBV treatment in chronic HCV patients were retrieved from PubMed. Data of qualified studies on sustained virological response (SVR) in different genotypes were extracted and analyzed using meta-analysis method in Stata 10 software. Thirty-four papers, containing 46 independent studies, were included in the analysis. In the HCV G1/4 patients without treatment history, individuals carrying rs12979860 CC genotype were more likely to achieve SVR (OR 3.97, 95%CI 3.29-4.80) compared to those carrying CT/TT genotypes. Similar results were observed in the HCV G1/4 patients with unsuccessful or unknown treatment history (OR 3.76, 95%CI 2.67-5.28) or in the patients co-infected with human immunodeficiency virus (OR 5.20, 95%CI 3.04-8.90). However, associations could not be observed in HCV G2/3 patients. For rs8099917, similar results were obtained for genotype TT compared to genotypes TG/GG, indicating that TT genotype was significantly associated with better treatment response in patients infected with genotype 1 or 4 HCV, but not genotype 2 or 3 HCV. Polymorphisms of rs12979860 and rs8099917 near IL28B only associate with the treatment response to PegIFN/RBV in patients infected with HCV genotype 1 or 4 but not with genotype 2 or 3, irrespective of the previous treatment history or HIV co-infected status. Therefore, identification of IL28B genotypes is necessary only in patients infected with relatively difficult-to-treat genotype 1 or 4 HCV.PLoS ONE 09/2012; 7(9):e45698. DOI:10.1371/journal.pone.0045698
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ABSTRACT: PURPOSE: Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of the Janus kinase/signal transducer and activation of transcription pathway. The purpose of this study was to investigate the relationship between methylation of SOCS-1 and sustained virologic response (SVR) in chronic hepatitis C (CHC) patients treated with pegylated interferon (PEG-IFN)-alpha and ribavirin (RBV). METHODS: In total, 106 CHC patients treated with PEG-IFN-alpha and RBV were included. Serum samples were obtained at baseline (P), end of treatment (EOT), and 6 months post treatment (F6). Methylation status of the promoter region of SOCS-1 was examined by quantitative methylation specific PCR (qMSP). RESULTS: Median baseline methylation level of SOCS-1 was -0.95 log10 copies/mL, which increased to 0.57 log10 copies/mL at EOT and then returned to -0.57 log10 copies/mL at F6 (baseline vs EOT, P < 0.001; EOT vs F6, P < 0.001). The overall SVR was 75.5 %. Univariate analysis indicated that SVR was significantly associated with genotype, baseline HCV RNA, body mass index (BMI) and higher EOT SOCS-1 methylation. Multivariate analysis confirmed that the SVR was significantly associated with genotype (OR: 13.40, 95 % CI: 1.73-103.58, P = 0.013), baseline HCV RNA (OR: 0.19, 95 % CI: 0.06-0.59, P = 0.004), BMI (OR: 0.73, 95 % CI: 0.56-0.96, P = 0.022), and EOT SOCS-1 methylation (OR: 1.71, 95 % CI: 1.11-2.62, P = 0.014). CONCLUSION: CHC patients with significantly higher SOCS-1 methylation at the end of treatment had better SVRs. The role of SOCS-1 methylation in affecting treatment response deserves further investigation.Journal of Clinical Immunology 05/2013; 33(6). DOI:10.1007/s10875-013-9903-4
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ABSTRACT: Background Since 2009, several studies have identified single-nucleotide polymorphisms (SNPs) near the gene encoding for interleukin (IL)-28 (IL28B) that are strongly associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Because this large amount of data includes some inconsistencies, we consider assessment of the global estimate for each SNP to be essential. Methods Relevant studies assessing IL28B polymorphisms associated with sustained virologic response (SVR) and spontaneous clearance (SC) were identified from a literature search of PubMed up to 9 July, 2012. Studies were eligible studies if they included patients infected with HCV or HCV/HIV, or assessed any SNP located within or near the IL28B gene, SVR data available under standard treatment, and/or SC data in patients with acute HCV infection. Pooled odds ratios were estimated by fixed or random effects models when appropriate. Variables such as HCV genotype, ethnicity, and type of co-infection were studied. Results Of 282 screened studies, 67 were selected for SVR and 10 for SC. In total, 20,163 patients were studied for SVR and 3,554 for SC. For SVR, we found that all SNPs showed strong associations in patients with HCV genotypes 1 and 4, whereas the pooled ORs were almost three times lower for genotypes 2 and 3 (rs12979860 and rs8099917). Regarding ethnicity, the SNP most associated with SVR was rs12979860 in white patients, whereas in East Asians it seemed to be rs8099917. The most studied SNP (rs12979860) showed similar results for patients co-infected with HCV/HIV, as for those infected with HCV only. Finally, rs12979860 and rs8099917 both appeared to be associated with SC. Conclusions IL28B polymorphisms influence both the outcome of interferon treatment and the natural clearance of HCV. However we did not identify a universal predictor SNP, as the best genetic markers differed depending on patient ethnicity, genotype, and type of infection. Nevertheless, our results may be useful for more precise treatment decision-making.BMC Medicine 01/2013; 11(1):6. DOI:10.1186/1741-7015-11-6